Formulation of pharmaceutical dosage forms is frequently hampered by poor aqueous solubility and/or stability of the drug of interest, which in turn can severely limit its therapeutic application. Conversely, increasing drug solubility and stability through appropriate formulation can accordingly lead to increased therapeutic efficacy of the drug. Various methods have been used to increase the solubility and stability of drugs such as the use of organic solvents, emulsions, liposomes and micelles, adjustments to pH and the dielectric constant of formulations solvent systems, chemical modifications, and complexation of the drugs with appropriate complexing agents such as cyclodextrins.
Cyclodextrins, sometimes referred to as Schardinger's dextrins, were first isolated by Villiers in 1891 as a digest of Bacillus amylobacter on potato starch. The foundations of cyclodextrin chemistry were laid down by Schardinger in the period 1903-191 1. Until 1970, however, only small amounts of cyclodextrins could be produced in the laboratory and the high production cost prevented the usage of cyclodextrins in industry. In recent years, dramatic improvements in cyclodextrin production and purification have been achieved and cyclodextrins have become much less expensive, thereby making the industrial application of cyclodextrins possible.
Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on the outer surface and a void cavity in the center. Their outer surface is hydrophilic, and therefore they are usually soluble in water, but the cavity has a lipophilic character. The most common cyclodextrins are .alpha.-cyclodextrin, .beta.-cyclodextrin and .gamma.-cyclodextrin, consisting of 6; 7 and 8 .alpha.-1,4-linked glucose units, respectively. The number of these units determines the size of the cavity.
Cyclodextrins are capable of forming inclusion complexes with a wide variety of hydrophobic molecules by taking up a whole molecule (a "guest molecule"), or some part of it, into the void cavity. The stability of the resulting complex depends on how well the guest molecule fits into the cyclodextrin cavity. Common cyclodextrin derivatives are formed by alkylation (e.g., methyl-and-ethyl-.beta.-cyclodextrin) or hydroxyalkylation of the hydroxyethyl-derivatives of .alpha.-, .beta.-, and .gamma.-cyclodextrin) or by substituting the primary hydroxyl groups with saccharides (e.g., glucosyl- and maltosyl-.beta.-cyclodextrin). Hydroxypropyl-.beta.-cyclodextrin and its preparation by propylene oxide addition to .beta.-cyclodextrin, and hydroxyethyl-.beta.-cyclodextrin and its preparation by ethylene oxide addition to .beta.-cyclodextrin, were described in a patent of Gramera et al. (U.S. Pat. No. 3,459,731, issued August 1969) over 20 years ago.
Although cyclodextrins have been used to increase the solubility, dissolution rate and/or stability of a great many compounds, it is also known there are many drugs for which cyclodextrin complexation either is not possible or yields no advantages. See J. Szejtli, Cyclodextrins in Drug Formulations: Part II, Pharmaceutical Technology, 24-38, August, 1991.
It is conventionally believed that a salt of a drug dissolves in a cyclodextrin-containing aqueous medium by simply dissociating to form a charged drug molecule and a counter-ion, and that it is the dissociated (charged) drug molecule which acts as a guest moiety and forms inclusion complexes with the cyclodextrin. A consequence of this is the belief that there are no differences in equilibrium solubility among the salts of a given drug in a specific cyclodextrin. Thus, if a solubility-phase diagram is generated for a particular drug in a particular aqueous cyclodextrin (i.e., a plot of the equilibrium solubility of a drug salt in the aqueous cyclodextrin as a function of cyclodextrin concentration), different salts of the drug should plot out as lines having the same slope.
The present invention is based, inter alia, on the determination that the solubility of the compounds presented below form stable inclusion complexes with cyclodextrins, and that such inclusion complexes are highly water soluble relative to the non-complexed drug.
The present invention is further based on the unexpected and surprising discovery that, in a particular cyclodextrin, there are solubility differences among particular salts of the aryl-heterocyclics useful herein. A particular salt of a specific aryl-heterocyclic can exhibit much greater solubility in a particular aqueous cyclodextrin solution than a different salt of the same aryl-heterocycle in the same cyclodextrin. Some salts show unexpectedly high solubility. Many, if not all, of the salts investigated for this invention exhibited their own distinctive slope when plotted on a solubility-phase diagram.
In the particular case of the aryl-heterocyclic ziprasidone, it has been determined that the order of solubility (e.g., the increasing order of solubility) of a series of different ziprasidone salts in aqueous cyclodextrin solution does not necessarily correlate with the order of solubility of those same salts in water.